The present invention relates to 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium hemipentahydrate and monohydrate, compositions containing said hemipentahydrate and/or monohydrate and methods of selective crystallization of the hemipentahydrate or monohydrate.
Bisphosphonates such as 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (RISEDRONATE) have been proposed for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. Paget""s disease and heterotropic ossification are currently successfully treated with both EHDP (ethane-1-hydroxy-1,1-diphosphonic acid) and RISEDRONATE.
The bisphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in biological activity, all bisphosphonates do not exhibit the same degree of biological activity. Some bisphosphonates have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or negative side effects in humans. The salt and hydrate forms of bisphosphonates alter both their solubility and their bioavailability.
It is known in the literature that some bisphosphonic acids and their salts are capable of forming hydrates, risedronate sodium exists in three hydration states: mono, hemipenta and anhydrous. Crystallization procedures which selectively yield the hemipentahydrate form or the monohydrate form are desirable. This application describes the hemipentahydrate and the monohydrate crystal forms, the compositions containing said hemipentahydrate and monohydrate crystal forms and selective formation of these crystals.
The present invention discloses 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium hemipentahydrate and monohydrate, compositions containing said hemipentahydrate and/or monohydrate and methods of selective crystallization of the hemipentahydrate or monohydrate. The temperature of nucleation and the rate of crystallization are the critical variables that control the ratio of hydrates formed.
The present invention is directed to a 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium hemipentahydrate and monohydrate and compositions containing said hemipentahydrate and monohydrate. A novel process is also disclosed for the selective crystallization of the geminal bisphosphonate, risedronate sodium, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium as the hemipentahydrate and as the monohydrate. 
Risedronate sodium, the mono sodium salt of risedronate, exists in three crystalline hydration states: anhydrous, mono and hemipentahydrate. The monohydrate and hemipentahydrate are preferred.
The hemipentahydrate is the thermodynamically preferred crystalline form under typical processing conditions based on the observation that monohydrate crystals converted to the hemipentahydrate form.
The monohydrate is by weight of water from about 5.0% to about 7.1%, more preferably from about 5.6% to about 6.5% and most preferably about 5.6%. The monohydrate is further characterized by single crystal X-ray crystallography, and thermogravimetric analysis. The monohydrate form also exhibits identifiable signatures when examined by X-ray powder diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy or near infrared spectroscopy.
The hemipentahydrate is by weight of water from about 11.9% to about 13.9%, more preferably from about 12.5% to about 13.2% and most preferably about 12.9%. The hemipentahydrate is further characterized by single crystal X-ray crystallography, and thermogravimetric analysis. The hemipentahydrate form also exhibits identifiable signatures when examined by X-ray powder diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy or near infrared spectroscopy.
The temperature of nucleation and the rate of crystallization are the critical variables that control the ratio of hydrates formed. The nucleation temperature can be controlled by controlling the ratio of water to solute, the solution temperature, and the ratio of organic solvent to water.
The risedronate sodium hemipentahydrate is the thermodynamically favored form under the typical processing conditions described. Compositions comprise by weight of risedronate sodium hydrate from about 50% to about 100%, more preferably from about 80% to about 100%, most preferably from about 90% to about 100% risedronate sodium hemipentahydrate and from about 50% to about 0%, more preferably from about 20% to about 0%, most preferably from about 10% to about 0% risedronate sodium monohydrate.
Altering the processing conditions as described can selectively produce the monohydrate crystal form. Compositions comprise by weight of risedronate sodium hydrate from about 50% to about 99%, more preferably from about 80% to about 99%, most preferably from about 95% to about 99% risedronate sodium monohydrate and from about 50% to about 1%, more preferably from about 20% to about 1%, most preferably from about 5% to about 1% risedronate sodium hemipentahydrate.
The invention further comprises pharmaceutical compositions containing the hemipentahydrate and monohydrate compounds.
The following is a list of definitions for terms used herein:
The term xe2x80x9crisedronatexe2x80x9d, as used herein, denotes 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and has the following structure: 
The compound risedronate is further described in U.S. Pat. No. 5,583,122, Benedict et al., assigned to the Procter and Gamble Co., issued Dec. 10, 1996, and xe2x80x9cAn American Conference, Bisphosphonates: Current Status and future Prospects,xe2x80x9d The Royal College of Physicians, London, England, May 21-22, 1990, organized by IBC Technical Services, both references hereby are incorporated by reference.
As used herein, xe2x80x9csolventxe2x80x9d, is a substance capable of dissolving another substance to form a uniform solution. The solvent may either be polar or non-polar. Solvents are selected from the group consisting of alcohols, esters, ethers, ketones, amides, and nitriles. Most preferred is isopropanol.
The process according to the present invention is characterized in that the process described herein is readily adapted to industrial production. The following non-limiting examples illustrate the processes of the present invention.
The extent of hydration 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium can be controlled by varying the crystallization parameters to control the temperature of nucleation and rate of crystallization. The ratio of hemipentahydrate to monohydrate crystal forms in the product can be effectively controlled by varying the water to 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium ratio and the isopropanol to water ratio as well as the temperature (see below).
General Procedure
An aqueous solution of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium at 0-75xc2x0 C., preferably 25-75xc2x0 C., more preferably 45-75xc2x0 C. will selectively yield either the monohydrate or the hemipentahydrate crystal forms depending upon the conditions of crystallization. The temperature of nucleation and the rate of crystallization governs the hydrate, varying the ratio of water: isopropanol and varying temperature and cooling ramp of the aqueous solution control the ratios of the hydration states formed.
Table 1 shows eight examples of reaction conditions which selectively produce 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium containing varying hemipenta to monohydrate ratios. The theoretical moisture level for the monohydrate is 5.6% and for the hemipentahydrate is 12.9%.